Manhoef was born in Paramaribo, Suriname. When he was three years old his family moved to Rotterdam, the Netherlands. Manhoef played soccer during his youth, and was introduced to Muay Thai by his younger brother, Moreno.

Melvin has switched his main focus to MMA over the past couple of years. He lost to Dong-sik Yoon by submission armbar in K-1 Dynamite!! USA, he defeated Bernard Ackah at K-1 Hero's Middleweight Tournament Opening Round, and also got a TKO win against Fábio Silva, a Chute Boxe fighter, by TKO in K-1 Hero's Middleweight GP Final. At Dream 4 Melvin fought Kazushi Sakuraba. Manhoef and Sakuraba circled the ring for the first minute of the fight, before Manhoef dropped Sakuraba with a hard right head kick and finished him via TKO (hammerfists) at 90 seconds into Round 1. With the win, Melvin had advanced to the semifinal round of the DREAM Middleweight Grand Prix. At Dream 6 Melvin fought Gegard Mousasi as the tournament dictated. Wary of Manhoef's standup, Mousasi quickly took the fight to the ground despite attempts to shrug him with a sprawl. Mousasi took Manhoef's back until scrambling into a triangle choke at 1:28 of the first round, surviving a powerful slam attempt from Manhoef while he had the submission secured. Mousasi went on to win the DREAM Middleweight Grand Prix.[6]

At Dynamite!! 2008 Melvin fought Mark Hunt as a late alternate at heavyweight, despite usually functioning at two weight classes below his opponent. Regardless of the size disadvantage, he knocked down the iron-jawed Samoan in 18 seconds and followed with punches as he was postured over Hunt, until the referee stopped the fight.[7] It was the first time Hunt was finished by knockout in his MMA career. He fought former WEC Middleweight ChampionPaulo Filho on 20 July 2009 at Dream 10.[8] Despite early success on the feet with his striking offensive, Manhoef was taken down and submitted via armbar in the first round.

Manhoef signed a multi-year fight contract with Strikeforce.[9]
Manhoef made his debut for the organization against Robbie Lawler on 30 January 2010 at Strikeforce: Miami. Despite a strong start with heavy leg kicks and punches, he was knocked out at 3:33 in the first round.

On 31 January 2012 it was announced that Manhoef had signed with ONE Fighting Championship and would be fighting Renato Sobral in the main event at ONE Fighting Championship 3.[12] However, Sobral pulled out of the fight and Manhoef faced Yoshiyuki Nakanishi. The fight ended in a No Contest due to an accidental injury to Manhoef's leg in round 1. Manhoef scored a knockout victory on 6 October 2012 against Ryo Kawamura, followed by a quick knockout of Dennis Kang on 31 December 2012. Melvin is now on a three-fight win streak in MMA and has gone 4–0 on New Year's Eve.

In 2013 Manhoef fought UFC veteran Brock Larson at ONE FC on 5 April. After controlling the standup and Larson literally running away from him, Manhoef was repeatedly taken down in the last two rounds and Larson won via unanimous decision. He lost to Mamed Khalidov at KSW23 on 8 June 2013.

He lost to Zabit Samedov by unanimous decision in the semi-finals of the 93 kg/205 lb kickboxing tournament at Legend 2: Invasion in Moscow, Russia on 9 November 2013.[13][14][15]

Manhoef faced Evangelista Santos in a much-anticipated rematch for the Gringo Super Fight Welterweight title on 27 April.[16] The fight was Melvin's first at 170 lbs. Manhoef won the bout via TKO, early in the first round.

Manhoef made his Bellator debut against Doug Marshall, in a middleweight bout, at Bellator 125 on 19 September 2014.[23] He won the fight via knockout in the first round.

Manhoef faced Glory veteran Joe Schilling on 15 November 2014 at Bellator 131.[24] After a dominant first round that saw Manhoef drop Schilling twice, he lost the fight in the second round due to a knockout.

Manhoef next faced Alexander Shlemenko on 13 February 2015 at Bellator 133.[25] He lost via knockout early in the second round. On March 17, 2015, Shlemenko was suspended indefinitely for failing a post fight drug test with elevated testosterone levels. The fight result was changed to a no contest.[26]

Manhoef faced Rafael Carvalho on 20 May 2016 for the Bellator Middleweight Championship at Bellator 155.[27] Manhoef lost a controversial split decision. Bellator announcer Jimmy Smith called it one of the worst decisions he had ever seen in the promotion; likewise, 5 of 5 media outlets scored the bout in favor of Manhoef.[28]

An immediate rematch with Carvalho was scheduled to take place at Bellator 168, on December 10, 2016.[29] However, Carvalho pulled out of the fight due to injury.[30] The rematch eventually took place on April 8, 2017 at Bellator 176. Manhoef lost the bout via knockout due to a head kick in the fourth round.[31]

Manhoef made a comeback to kickboxing and faced Remy Bonjasky for the fourth time, after losing three times, on October 29, 2017. Manhoef won the bout by decision. He announced his retirement from kickboxing and stated that he would focus on his MMA career.[32]

In May 2018 it was revealed that Manhoef and Bellator had come to terms for an exclusive, multi-fight contract.[33]

Manhoef was scheduled to face Chidi Njokuani on on November 30, 2018 at Bellator 210.[34] However, on November 1, 2018 it was reported that Manhoef pulled out from the event due to injury and he was replaced by John Salter.[35]